The objective of this study was to determine the morbidity, mortality and diagnostic yield of video assisted thoracoscopy (VATS) and thoracotomy lung biopsy in interstitial lung disease (ILD). Clinical records of 71 patients were retrospectively analyzed. There was no difference in mean hospital stay, intensive care unit stay and duration of chest tube drainage in patients with VATS (n = 52) compared with those undergoing open thoracotomy (n = 17). Complications rate (22.2% vs. 21.0%, p = 1.0000) and operating mortality (9.2 vs. 15.7%, p = 0.2738) were also similar. Overall, complications occurred in 16 patients (22.5%). Thirty-day mortality rate was 11.2% (n = 8). Prevalence of immunosupression (4/8 vs. 9/63, p = 0.0325) was significantly higher in the group of patients who died. No surviving patients had higher values of plasmatic urea (50 +/- 20.1 mg/dl vs. 31.2 +/- 10.3 mg/dl, p = 0.0013) or lower values of preoperative oxygen saturation (SaO2): 82.7 +/- 14.8% vs. 92.8 +/- 3.4%, (p = 0.0009). Eleven patients had an acute illness. Those patients did not show a higher complication rate (4/11 vs. 10/45, p = 0.4390) but mortality was significantly higher (4/11, 36.3% vs. 3/45, 7.1%, p = 0.0223). Biopsy allowed a specific histologic diagnosis in 100% of patients and changed therapy in 66.7%. We conclude that surgical lung biopsy is a safe and useful procedure in patients with ILD. However the higher mortality rate in patients with acute symptoms, immunocompromise, or in respiratory failure must be balanced against potential benefits of altering treatment decisions.